In this application p53, is taken as a representative example of an ubiquitously expressed self-antigen known to be associated with cancer. The strategy used to design a vaccine against p53 could be applied to design a vaccine against any other ubiquitously expressed self-antigen known to be associated with cancer.
The nuclear phosphoprotein p53 is a tumor suppressor protein that is ubiquitously expressed at low levels in normal tissues, including thymus, spleen and lymphohematopoetic cells (Rogerl A et al, Milner J et al, Terada N et al). The normal half-life of wild-type p53 is less than 30 minutes. Following ubiquitination, the wild-type (WT) p53 protein is rapidly degraded by proteasomes (Honda R et al, Momand J et al, Shkedy D et al). Proteasome-mediated digestion of p53 may lead to the generation of peptides that are presented by class I MHC molecules. Recognition of these class I MHC bound wild-type p53 derived peptides at the surface of thymic APC by immature thymic T-cells with high avidity for the class I MHC-peptide complex will result in negative selection (Allen P M et al, Ashton-Rickardt P G et al, Kappler J W et al). As a consequence, the peripheral T-cell repertoire will not contain functional p53-specific class I MHC-restricted T-cells. Theobald et al. elegantly showed that CTL specific for the naturally processed peptide p53187-197 were deleted from the repertoire in WTp53 mice but not in p53−/− mice (Theobald M et al, 1997), demonstrating that negative selection of high avidity p53-specific CTL can occur in the thymus. Paradoxically, class I MHC-restricted CTL able to recognize endogenously processed WTp53 at the surface of tumor cells, have been detected in both mice and man (Theobald M et al 1997, Macagno A, et al, Mayordomo J I et al, Barfoed A M et al, Chikamatsu K et al, Eura M et al, Houbiers J G et al, Ropke M et al) suggesting that functional p53-specific class I MHC-restricted CTL can escape from tolerance induction.
Several p53 vaccines have already been developed. For example, WO 00/75336 discloses polyepitopic peptides derived from p53 having the capacity to be degraded by the proteasome and to associate with high affinity to class I MHC molecules. Such properties are supposed to be essential for inducing an immune response against p53. More likely, T-cells responding to this type of peptides have either been deleted in the thymus, are tolerized in the periphery or are of low T-cell receptor affinity to mediate an effective anti-tumor response (Theobald M & Offring a R. 2003, and Morgan et al.) Thus, it is to be expected that such peptides derived from an ubiquitously expressed self-antigen, such as p53, will not be able to trigger a strong and effective immune response in vivo.
Therefore, there is still a need for new and improved p53 vaccines, which does not have all the drawbacks of existing p53 vaccines.